The compound 1,1′-[1,4-phenylenebis (methylene)]-bis [1,4,8,11-tetraazacyclo tetradecane], also known as plerixafor is represented by the Formula (I):

Plerixafor (marketed under the trade name Mozobil, Genzyme Corporation) is a hematopoietic stem cell mobilizer and is inhibitor of the CXCR4 chemokine receptors. It was approved by the U.S. Food and Drug Administration (FDA) on 15 Dec. 2008 to mobilize hematopoietic stem cells (HSCs) to the peripheral blood for collection and subsequent autologous transplantation in patients with non-Hodgkin's lymphoma and multiple myeloma.
Plerixafor, as represented by Formula (I) was first reported by Ciampolini et al. in Inorg. Chem, 1987, 26 (21), pp 3527-3533.
Various processes for the preparation of plerixafor have been described in literature. Conventionally, the compound of formula (I) is prepared by selective functionalization of the cyclam ring, followed by reaction with α,α′-dihalo-p-xylene and dimerization. The product is deprotected to obtain the compound of formula (I) which is further purified by recrystallization in various solvents.
WO 93/12096 describes the synthesis of different xylene linked polyamine macrocyclic compounds as explained above, wherein the cyclam ring is tosyl protected and reacted with an activated xylene diol intermediate to obtain an intermediate which is purified by column chromatography and deprotected to obtain the final product.
A similar process for the synthesis of compound of formula (I) is described in the WO 00/28987. The synthetic scheme is depicted below as scheme-1:

Cyclam is reacted with p-toluene sulfonyl chloride in the presence of triethylamine to obtain tris-(p-toluenesulfonyl)-1,4,8,11-tetraazacyclotetradecane in 33% yield. This tosyl protected cyclam ring is reacted with α,α′-dibromo-p-xylene in the presence of base in solvent at reflux temperature to give 1,1′-[1,4-phenylenebis(methylene)]-bis[4,8,11-tris-(p-toluene sulfonyl)-1,4,8,11-tetraazacyclotetradecane which is purified by chromatography. Finally this intermediate is subjected to hydrolysis in a mixture of acetic acid and hydrobromic acid to afford the final compound as octahydrobromide salt, the purity of which is not mentioned.
Further, WO 2014/125499 also describes a similar process for the preparation of plerixafor. Cyclam is protected with tosyl groups in the presence of triethylamine in dichloromethane. The yield is 36.4%. The resulting compound was reacted with α,α′-dibromo-p-xylene in the presence of potassium carbonate in dimethylformamide. The yield is 40%. Deprotection of this intermediate in the presence of acetic acid and hydrobromic acid gives plerixafor octahydrobromide dihydrate in 90.3% yield.
The above mentioned synthetic processes do not afford the intermediate compounds in good yield or purity. Column chromatography is required to purify the intermediates and therefore a significant amount of yield is lost.
In WO 02/26721A1, the authors disclose a process for the preparation of plerixafor base using ethyl trifluoroacetate as protecting reagent instead of p-toluene sulfonyl chloride. The reaction scheme is summarized below in scheme-2.

Cyclam is reacted with ethyl trifluoroacetate in the presence of triethylamine in methanol to give tris trifluoroacetyl cyclam. The resulting compound is isolated by column chromatography technique. The yield is 92.5%. The purity of the compound is not mentioned. The compound is coupled with α,α′-dichloro-p-xylene in the presence of potassium carbonate and potassium iodide in acetonitrile at reflux temperature to get the product in 85% yield. Here also compound purity is not mentioned. Deprotection of trifluoro acetyl group of the product is carried out by treatment with potassium carbonate in methanol to afford plerixafor base in 86% yield. The compound is isolated from toluene but the purity is not mentioned.
This process gives better yield but the purity of the intermediates or of plerixafor base is not mentioned. Also, column chromatography is required for the isolation of the tris trifluoroacetyl cyclam intermediate. Column chromatography, needless to say, is a tedious process which makes this route unfit for commercial purposes.
Indian patent application IN2011CH2459 describes a process for the preparation of plerixafor using tert-butoxycarbonyl as the protecting group. The reaction scheme is summarized below in scheme 3:
wherein, “Boc” means tert-butoxycarbonyl. Cyclam is reacted with di-tert-butyl dicarbonate in methylene chloride to give tris-Boc protected cyclam. The compound is reacted with α,α′-dibromoxylene in the presence of potassium carbonate in acetonitrile to yield 1,1′-xylyl-bis [4,8,11-tris(tert-butoxycarbonyl)-1,4,8,11-tetraazacyclotetradecane]. The resulting compound is subjected to treatment with 1N hydrochloric acid and later with sodium hydroxide to obtain plerixafor, which is crystallized from acetone. The purity of final compound or intermediates is not mentioned and the overall yield is extremely low.
The inventors of the present invention have found that in all the above mentioned processes the purity of intermediate compounds is very low leading to significant yield losses during purification. A possible reason for such high amount of impurity formation appears to be the presence of four secondary nitrogen atoms in cyclam, out of which only three need to be protected. But during the reaction of cyclam with p-toluene sulfonyl chloride, Boc anhydride or ethyltrifluoroacetate, mono, di, tri and tetraprotected cyclam is formed. The structures of these are as shown below:
wherein PG represents a protecting group like Tosyl or Boc etc.
Such mono- or di-protected cyclam rings will give side reactions leading to further impurities while the tetra protected cyclam will remain unreacted as an impurity in the subsequent steps. These impurities are difficult to remove and result in low yield and purity of further steps as well.
New J. Chem. 2001, 25, 1168-1174, describes an alternative process for the preparation of plerixafor. The cyclam ring is protected with the help of glyoxal, the protected cyclam ring is then reacted with dibromo-p-xylene to yield an intermediate which is deprotected with the help of hydroxylamine hydrochloride and sodium ethoxide to yield the final compound. The overall synthesis is shown in scheme-4:

The glyoxal protection of the cyclam ring prevents the formation of mono, di or tetra-protected impurities and therefore it is expected that the yield and purity of the final compound be better than those of the other processes.
However, it was found that the purity of plerixafor obtained via this process is very low. It was further found by the inventors that the glyoxal protected cyclam is a low melting and hygroscopic solid which is impossible to isolate or purify.
Any process generated impurities are carried forward to the next stages leading to an impure final compound.
Also, the final deprotection reaction involves the use of the hazardous, difficult to handle and hygroscopic reagent, sodium ethoxide. The use of strong reagents like sodium ethoxide leads to large amounts of impurity formation. Thus the final compound obtained by this process has very low purity.
Various inorganic bases have been described in literature for the removal of bis-aminal bridge from the cyclam moiety. J. Org. Chem., 2005, 70, 7042-7053 describes the use of sodium hydroxide for the deprotection of cyclam rings from plerixafor. But no information about the quality or purity of the product is mentioned.

From the foregoing, it is apparent that the reported methods for the preparation of plerixafor suffer from one or more of the following drawbacks:                (a) extensive column chromatography needed to purify the intermediates used in the process,        (b) low yields obtained due to the formation of impurities, and        (c) use of hazardous and moisture sensitive reagents.        
Thus, there still remains the need to formulate an efficient, simple and industrially viable synthetic process which can overcome the drawbacks of the prior art and which provides plerixafor and its intermediates free of impurities.